3,510,561 United States Patent Office Patented May 5, 1970 1. 2 3,510,561 of anticoagulant activity in the blood. Such repeated in SULFONE-ENHANCED HEPARN ABSORPTION jections are both inconvenient and painful. THROUGH MUCOUS MEMBRANES Teow Yan Koh, Toronto, Ontario, Canada, assignor to THE INVENTION Canada Packers Limited, Toronto, Ontario, Canada No Drawing. Continuation-in-part of applications Ser. No. 5 The invention in its broad aspect resides in the dis 457,501 and Ser. No. 457,502, both filed May 20, 1965, covery that certain sulfones enhance or promote the ab Ser. No. 550,935, May 18, 1966, and Ser. No. 686,323, Sorption of heparin through the mucous membranes, such Nov. 28, 1967. This application Aug. 18, 1969, Ser. No. as the Sublingual regions of the mouth and the walls of 851,102 the intestinal tract. By combining heparin with the sul Int, C. A61k 17/18 10 fone, the use of this highly regarded anticoagulant sub U.S. C. 424-183 26 Claims stance is extended to oral administration and to adminis tration to other mucous membranes. See U.S. Pat. No. 3,062,716 granted Nov. 6, 1962 for administration of ABSTRACT OF THE DISCLOSURE heparin rectally and U.S. Pat. No. 3,232,833, granted 15 Feb. 1, 1966, for administration of heparin to the mucous This invention relates to sulfone-enhanced heparin membranes of the eye, ear, nose and throat. absorption through mucous membranes and particularly The expression "oral administration' as used herein, to compositions and methods for administering heparin means administration by mouth and includes introduction so that it is absorbed through the mucous membranes to of the therapeutic compositions of the invention into the provide effective anticoagulant activity. The compositions 20 Sublingual or buccal regions for absorption therefrom, as contain heparin and at least one non-toxic physiologically well as the administration in the form of enteric-coated acceptable sulfone, such as a dialkylsulfone, a sulfolane or tablets or capsules for swallowing and subsequent release sulfolene. It has been discovered that these sulfones pro of the heparin in the intestine for absorption through the mote the absorption of the heparin anticoagulant sub intestinal walls. stance through the mucous membranes. The compositions 25 Use of the invention is in the fields for which heparin may also contain a fatty alcohol of chain length C14 to C24 therapy has already been established and may be in the to prolong or regulate the time period of absorption of veterinary field for the therapeutic treatment of animals. the active anticoagulant substance from the composition. The invention, in a further aspect, resides in the dis The composition may be administered in the form of covery that certain saturated and unsaturated fatty al solids or liquids which may be incorporated in enteric 30 cohols and mixtures thereof, preferably of chain length coated tablets or capsules for oral administration. C14 to C2a, when administered simultaneously with hep arin and a sulfone, improve and sustain the effectiveness of the anticoagulant activity. This represents a substantial The present application is a continuation-in-part of my advantage in anticoagulant therapy, where a sustained applications Ser. Nos. 457,501 and 457,502, filed May 20, 35 action is very desirable. Repeat dosages may be adminis 1965, now abandoned, my application Ser. No. 550,935 tered at longer time intervals and a more uniform re filed May 18, 1966 now abandoned and my application sponse attained. Ser. No. 686,323 filed Nov. 28, 1967. An object of the invention is to provide a heparin com 40 position which is effective when administered to the mu BACKGROUND AND DEFINITIONS cous membranes, including administration by the oral The invention relates to heparin compositions and route. methods of administration. Another object is to provide an improved heparin com The word “heparin' as used in the present application position from which the anticoagulant activity is absorb refers to the readily water soluble forms of the natural 45 able into the blood stream from the intestinal tract. sulfated polysaccharides composed of alternating hexos Another object of the invention is to provide a heparin amine and hexuronic residues including the non-toxic composition from which the anticoagulant activity is ab water soluble salts and water soluble derivatives thereof. sorbable from the intestinal tract over a Sustained period While the invention is exemplified with the sodium salt, of time. it is understood that other water soluble heparin com 50 Another object of the invention is to provide a heparin pounds known to the art, including other alkali metal salts composition which may be administered orally and from as well as organic salts, such as choline heparinate and which the anticoagulant activity can be slowly but con procaine heparinate may be used. See for example, U.S. tinuously absorbed through the mucous membranes. Pat. No. 3,062,716 granted Nov. 6, 1962, for a disclosure A still further object of the invention is the provision of of various heparin salts. 55 orally effective heparin compositions which are easy to Heparin has a long established reputation as a safe and encapsulate. effective anticoagulant. Its use, however, has been limited Suitable sulfones for the purposes of this invention by the need to administer it parenterally, since it is in are the non-toxic, pharmaceutically-acceptable sulfones active or only slightly active per se by routes other than which are substantially devoid of undesirable physiologi parenteral, for example by the oral route. (See, for ex 60 cal activity. Reference is made to U.S. Pat. No. 3,098,793, ample, the article by Windsor et al. entitled "An investi granted July 23, 1963, describing the known utility of gation of Routes of Administration of Heparin Other certain sulfones as pharmaceutical solvents for a wide Than Injection' in American Journal of Medicine, vol. variety of difficultly soluble medicinal agents. 37, September 1964, pages 408-416, wherein sublingual, Examples of the sulfones which enhance the absorp buccal, rectal and pulmonary routes using tablets, solu 65 tion of heparin through mucous membranes are those tions, suppositories and aerosols were reported.) Injec of the formula tions have been characterized by a quick response to pro RRSO vide a high level of systemic anticoagulant activity which wherein R1 and R2 are alkyl, alkylene, aralkyl, or to then declines at a rapid rate. Therefore, repeated intra gether form with the sulfur atom a saturated or unsatu venous injections or large subcutaneous injections are re 70 rated five or six membered ring such as in sulfolane and quired where it is desired to maintain a therapeutic level sulfolene. R1 and R2 may be the same or may be different. 3,510,561 3 4 Specific examples are the di-alkyl sulfones having the compositions of the invention is readily determined by formula: those skilled in the art. For example, sufficient of the composition is administered orally in one or more tab (I) R1 O lets or capsules to double the blood clotting time as deter N mined on a sample of withdrawn blood of the particular S species of mammal undergoing treatment. If the thera R^ O peutic level is to be maintained the dosage is repeated at intervals as deemed necessary. wherein R1 and R2 are alkyl or aralkyl (e.g. benzyl) Representative therapeutic dosages may contain, for groups having up to 12 carbon atoms. example, 50 to 100 mg. of heparin having an activity Examples of ring compounds are sulfoilane (tetrahydro O of 100 anticoagulant u/img., and from about 0.5-10grams thiophene 1,1-dioxide) having the formula: of the selected sulfone per 100 mg. of heparin. From 0.1 to 2 grams of fatty alcohol may be included. If water (II) O is included in the composition, the amount can vary 5 over wide limits, e.g. from 0 to 90%. The total daily unit of heparin for a mammal, such as a dog, may, for example, be from 50-1000 mg. (based (wherein a is a single bond), sulfolene (wherein a of on heparin having an activity of 100 u/mg.) in com Formula II. is a double bond), and their homologues and bination with from 0.5 to 10 grams of the sulfone and, close analogues, e.g. wherein one or more of the hy 20 if desired, from 0.1 to 10 grams of the fatty alcohol. drogen atoms may be substituted by hydrocarbon radi Because of the well-known instability of heparin in acids, cals as described in U.S. Pat. No. 2,360,861. standard enteric encapsulation procedure as set forth, for The fatty alcohols of chain length C14 to C4 are ex example, in Remington's Practice of Pharmacy, or in emplified by cetyl alcohol (C16), stearyl alcohol (C18), U.S. Pat. No. 3,126,320, granted Mar. 24, 1964, e.g. oleyl alcohol (C18), arachidyl alcohol (C20), behenyl 25 with cellulose acetate phthalate, or the like, is used to alcohol (C2) and mixtures thereof which are obtain provide an enteric capsule which when swallowed will able, for example, by reduction of corresponding fatty Survive the acid medium of the stomach and will be acids. The fatty acids themselves are ineffective. The dissolved in the alkaline medium of the intestine. As fatty alcohols of the chain length specified may either an example of this mode of administration, the dosage be saturated or unsaturated, e.g. oleyl alcohol. They 30 unit sufficient to double blood clotting time is given in possess good emulsifying properties. Further, it has been the form of one or more enteric-coated gelatin capsules.